Preparation of1,4-disubstituted-2(1h)-quinazolinones

ABSTRACT

THE PREPARATION OF 1-SUBSTITUTED-4-ARYL-2(1H)-QUINAZOLINONES, E.G. 1-ISOPROPYL-7-METHYL-4-PHENYL-2(1H)QUINAZOLINONE, BY REACTION OF 2-SUBSTITUTED AMINOBENZOPHENONE WITH UREA IN THE PRESENCE OF A LOWER CARBOXYLIC ACID. THE QUINAZOLINATES ARE USEFUL AS PHARMACEUTICAL AGENTS, E.G. AS ANTI-INFLAMMATORY AND ANALGESIC AGENTS.

3,793,324 PREPARATION OF 1,4-DISUBSTITUTE 2(1H)-QUINAZOLINONES MaxDenzer, 288 Kingston Road,

Lake Parsippany, NJ. No Drawing. Filed Nov. 18, 1971, Ser. No. 200,141

7 Claims Int. Cl. C07d 51/48 US. Cl. 260-251 QB ABSTRACT OF THEDISCLOSURE The preparation of 1-substituted-4aryl-2(lH)-quinazolinones,e.g. 1-isopropyl-7-methyl-4-phenyl-2(1H)- quinazolinone, by reaction of2-substituted aminobenzophenone with urea in the presence of a lowercarboxylic acid. The quinazolinones are useful as pharmaceutical agents,e.g. as anti-inflammatory and analgesic agents.

The present invention relates to the preparation of 1-substituted-4-aryl-2(1 H)-quinazolinones from 2-substitutedaminobenzophenones by reacting the latter with urea in the presence of alower carboxylic acid.

The preparation of 1-substituted-4-aryl-2(1H)-quinazolinones by reactinga Z-substituted aminobenzophenonc with urea in the presence of a Lewisacid at relatively high temperatures of the order of about l80-200 C.has previously been described but such preparation has been subljgct todisadvantages and resulted in only moderate y1e s.

A major object of the present invention is to provide a new and improvedprocess for the preparation of lsubstituted-4-aryl-2(1H)-quinazolinonesfrom 2-substituted aminobenzophenones and urea.

In accordance with the present invention, it has been found that1,4-substituted-Z(1H)-quinazolinones of the General Formula I:

wherein R represents hydrogen, halo of atomic weight of from 18 to 80,i.e., fluoro, bromo and chloro; lower alkyl containing 1 to 3 carbonatoms; lower alkoxy containing 1 to 3 carbon atoms; nitro; loweralkylthio of 1 to 3 carbon atoms; or trifluoromethyl;

R represents hydrogen, halo, lower alkyl or lower alkoxy, as definedabove; or

R and R together represent 6,7-methylenedioxy;

R represents lower alkyl containing from 1 to 5 carbon atoms, e.g.methyl, ethyl, propyl, isopropyl, butyl, secbutyl and isobutyl;cycloalkyl of 3 to 6 carbon atoms; cycloalkylalkyl of 4 to 7 carbonatoms in which the cycloalkyl contains from 3 to 6 carbon atoms; allyl;methallyl; or propargyl, provided that R does not represent a tertiaryalkyl in which the tertiary carbon atom is attacheddirectly to the ringnitrogen atom;

R" represents phenyl, or substituted phenyl of the formula Y representshalo of atomic weight from 18 to 80; lower alkyl containing from 1 to 3carbon atoms, e.g. methyl,

Patented Feb. 19, 1974 lower alkoxy containing from 1 to 3 carbon atoms,e.g. methoxy; or trifluoromethyl;

Y' represents hydrogen, halo of atomic weight of from 18 to lower alkylcontaining from 1 to 3 carbon atoms, e.g. methyl, lower alkoxycontaining from 1 to 3 carbon atoms, e.g. methoxy;

are prepared by cyclizing a 2-aminobenzophenone of the Formula H:

in which R, R", R and R" are as defined above, with excessurea in thepresence of a lower carboxylic acid at temperatures of at least 80 C.

The reaction of the present invention is carried out at temperatureswhich are suitably in the range of from at least 80 C. to 160 C.,preferably C. to C., and conveniently at the reflux temperature of thereaction system. Higher temperatures can be used, but it is one of theadvantages of the present invention that such are not necessary. Thehigh yields which characterize the present invention are obtained whenat least 3 mols of urea are employed per mole of compound of the Formula11. The upper limit of the amount of urea employed relative to thecompound of the Formula II is not particularly critical and molarexcesses of up to 20 or even more times the amount of Compound 11 may beused without substantially depreciating the high yields obtainable bythe process of the invention. Preferably, the mol ratio of urea toCompound His in the range of from 4:1 to 15:1, more preferably 5:1 to10:1.

The lower carboxylic acids employed in the process of the invention arethe monocarboxylic acids of 2 to 4 carbon atoms, e.g. acetic acid andpropionic acid, preferably glacial acetic acid. The lower carboxylicacid is employed as a solvent which also clearly has a beneficial effecton the process of the invention. The amount of the carboxylic acidemployed is important in achieving the desired results. At least about 2mols of acid per mol of urea must be used, preferably 4 to 1?. mols.There is no precise upper limit to the amount of acetic acid, but morethan 20 mols per mol of urea merely increases the volume of the reactionmixture without accompanying benefit.

In addition to the aforementioned starting materials, other agents suchas paratoluene sulfonic acid may be added.

The reaction is carried out until all or substantially all of theaminobenzophenone is consumed, as determined, for example, by analysisof the reaction mixture, as by thin layer chromatography. The reactiontime will, of course, depend on the reaction temperatures and therelative proportions of the reactants. Normally, it will range fromabout 1 to 20 hours.

The product can be recovered from the reaction mixture by conventionalmethods.

The compounds of Formula II used as starting materials in the foregoingreaction are either known, per se, or can be prepared from availablematerials by procedures known in the art.

The compound-s of structural Formula I are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful as anti-inflammatory agents as indicated by thecarrageenin-induced edema test on rats (oral administration). For suchuse, the compounds may be combined with a pharmaceutically acceptablecarrier, and such other conventional adjuvants as may be necessary, andadministered orally in such or parenterally in theformof an injectablesolution or suspension. The dosage administered will, of course, varydepending upon the compounds used and mode of administration. However,in general, satisfactory results are obtained when administered at adaily dosage of from about .15 milligram to about 100 milligrams perkilogram of body weight, preferably given in divided doses 2 to 4 timesa day, or in sustained release form. For

larger mammals, the administration of from about milligrams to about1000 milligrams of the compound per day provides satisfactory resultsand dosage forms suitable for internal administration comprises'fromabout 3 milligrams to about 500 milligrams of the compound in admixturewith a solid or" liquid pharmaceutical carrier or diluent.

The Compounds Iof the invention are also useful as analgesics asindicated by application of pressure to yeast-inflamed foot of the rat(oral administration). They are also useful as anti-pyretics asindicated by inhibition of bacterial lipopylsaccharide-induced fever(oral administration). Forsuch uses, the compound may be administered toobtain "satisfactory results at dosages and in modes similar to thoseemployed in the treatment of inflammation. j

The following examples illustrate the invention. Unless otherwiseindicated, temperatures are in centigrade degrees.

EXAMPLE 1 A mixture of 3.036 kg. of Z-N-isopropylamino-4-methylbenzophenone, 5.28 kg. urea and 30.6 kg. glacial acetic acid is heatedto reflux (115) for 4.5 hours. The reaction mixture is concentrated,under vacuum until no more acetic acid distills off, cooled to 50 anddissolved in 15.6 kg. chloroform. The resulting material is cooled toroom temperature and washed with water. The chloroform layer is washedand concentrated under vacuum to afford an oil which is crystallizedfrom ethylacetate to obtain 2.75 kg.1isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone, M.P. 140141. Thefiltrate is concentrated, cooled and washed to obtain an additional .17kg. of the product,

M.P. 140-141". Total yield 87.7%.

EXAMPLE 2 A mixture of 12.7 g. 2 -N-isopropylamino-4-methylbenzophenone, 25 ml. of glacial acetic acid, 12.3 g. urea and 2.3 g.p-toluenesulfonic acid is heated at reflux until thin layerchromatography indicates the absence of unreacted benzophenone. Afterremoval of the acetic acid, water and chloroform are added to thereaction mixture which is then made basic with ammonium hydroxide. Thechloroform layer is washed with water and the chloroform evaporated toleave an oily residue which is crystallized from ethylacetate and washedwith ether to give l-isopropyl-4-phenyl-7-methyl 2(1H) quinazolinone.Yield 70-80%.

Following the procedure of Example 1, but using an equivalent amount ofthe apprporiate aminobenzophenone there is obtained:

(g) 6-bromo-1-isopropyl-4-phenyl 2 1H -quinazolinone;

beingat least 2:1. 7

(h) l-allyl 7 chloro 4 M.P. v 173-174IC.

(i) 1-isopropyl-6-methoxy-4 phcnyl-2 1H) -quinazolinone;

M.P. 148-150 C.

(l) 1-isopropyl-7-methyl-4-(4-methoxyphenyl) 2(1H)- quinazolinone; M.P.16-3-165 C.

(k) 1' methyl 4 ('3 trifluoromethylphenyl) 2(1H)- quinazolinone; M.P.165'l67 C.

(l) l-mcthallyl 4 phenyl-2(1H)-quinazolinone; M.P.

(m) 6,7 dichloro 1 isopropyl 4 quinazolinone; M.P. 191-194 C.

(n) 'l-isopropyl 4 (rn-fluorophenyl) 6,7methylenedioxy-2(1H)-quinazolinone; M.P.' 169-l70 C.

(o) l isopropyl 4 phenyl 6,7 methylenedioxy- 2(lH) -quinazolinone; M.P.215218 C.

(p) 1-isopropyl-"4 (p-fluorophenyl) 6,7 methylene- Idioxy-2(lH)-'quinazolinone; M.P. 238-240 C.

(q) l-isopropyl 4 --(m-niethoxyphenyl) 6,7 methylenedioxy-2(1H)-quinazolinone; M.P. 189-19l C.

I What is claimed is:v A Q 1. A process for the preparation formula:

henyl-2( 1H) -quinazolinorie phenyl 2 iH)- of a compound of the whereinR represents hydrogen, halo of atomic Weight of from 18 to lower alkylof 1 to3 carbon atoms; lower alkoxy of 1. to 3 carbon atoms; nitro;lower alkylthio of 1 to 3 carbon atoms; or trifluoromethyl;

R represents hydrogen, halo, lower alkyl or lower alkoxy,

as defined above; or

R and R together represent 6,7-methylenedioxy;

R represents lower alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6carbon atoms; cycloalkylalkyl of 4 to 7 carbon atoms in which thecycloalkyl contains from 3 to 6 carbon atoms; allyl; methallyl; orpropargyl, pro vided R does not represent a tertiary alkyl in which thetertiary carbon atom is attached directly to the ring nitrogen atom;

R" represents phenyl; or substituted phenyl of the formula whichcomprises reacting a 2-substituted aminobenzophenone of the Formula II RNH- R C=O R" (II) in which R, R", R and R are as defined above, withurea in the presence of a saturated mono-carboxylic acid of 2 to 4carbon atoms at a temperature of at least 80 C. the mol ratio of urea toaminobenzophenone being at least 3:1 and the mol ratio of carboxylicacid to urea 2. A process for the preparation of a compound of theformula wherein R represents hydrogen, halo of atomic weight of from 18to 80; lower alkyl of 1 to 3 carbon atoms; lower alkoxy of 1 to 3 carbonatoms; nitro; lower alkylthio of 1 to 3 carbon atoms; ortrifluoromethyl;

R represents hydrogen, halo, lower alkyl or lower alkoxy,

as defined above; or

R and R together represent 6,7-methylenedioxy;

R represents lower alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6carbon atoms; cycloalkylalkyl of 4 to 7 carbon atoms in which thecycloalkyl contains from 3 to 6 carbon atoms; allyl; methallyl; orpropargyl, provided R does not represent a tertiary alkyl in which thetertiary carbon atom is attached directly to the ring nitrogen atom;

R" represents phenyl; or substituted phenyl of the formula Y representshalo of atomic weight of from 18 to 80; lower alkyl of from 1 to 3carbon atoms, lower alkoxy of from 1 to 3 carbon atoms, ortrifluoromethyl;

Y represents hydrogen, halo of atomic Weight from 18 to 80, lower alkylof 1 to 3 carbon atoms or lower alkoxy of 1 to 3 carbon atoms,

which comprises reacting a Z-substituted aminobenzophenone of theFormula II in which R, R, R' and R" are as defined above, with urea inthe presence of a mono-carboxylic acid of 2 to 4 carbon atoms selectedfrom the group consisting of acetic acid and propionic acid at atemperature of at least C. the mol ratio of urea to aminobenzophenonebeing at least 3:1 and the mol ratio of carboxylic acid to urea being atleast 2: 1.

3. The process of claim 2 wherein the reaction ten1- perature is in therange of 80 to C.

4. The process of claim 2 wherein the mol ratio of urea toaminobenzophenone is in the range of 5:1 to 10: 1.

5. The process of claim 2 wherein the mono carboxylic acid is aceticacid.

6. The process of claim 2 wherein the mol ratio of mono carboxylic acidto urea is in the range of from 4:1 to 10:1.

7. The process of claim 2 wherein the compound of Formula II is2-N-isopropylamino-4-methyl bcnzophenone.

References Cited UNITED STATES PATENTS 3,547,921 12/1970 Hardtmann etal. 260251 OTHER REFERENCES Armarego, Fused PyrimidinesPt.I--Quinazolines, Interscience Publishers (1967), p. 70.

NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, Assistant Examiner US.Cl. X.R.

